Auristatin compounds and conjugates thereof

Abstract

Auristatin compounds and conjugates thereof are provided herein. The conjugate comprises a protein based recognition-molecule (PBRM) and a polymeric carrier substituted with one or more -L D -D, the protein based recognition-molecule being connected to the polymeric carrier by L P . Each occurrence of D is independently an Auristatin compound. L D and L P are linkers connecting the therapeutic agent and PBRM to the polymeric carrier respectively. Also disclosed are polymeric scaffolds useful for conjugating with a PBRM to form a polymer-drug-PBRM conjugate described herein, compositions comprising the conjugates, methods of their preparation, and methods of treating various disorders with the conjugates or their compositions.

What is claimed is: 
     
       1. A compound of Formula (XIIb): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein
 R 42′  is —NH—R 40  or —O—R 42 ; 
 each of R 40  and R 42  independently is a substituted alkyl selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         in which a is an integer from 1 to 6 and c is an integer from 0 to 3. 
       
     
     
       2. The compound of  claim 1 , wherein R 42′  is —NH—R 40 , in which R 40  is 
       
         
           
           
               
               
           
         
       
     
     
       3. The compound of  claim 2 , wherein R 40  is 
       
         
           
           
               
               
           
         
       
     
     
       4. The compound of  claim 1 , wherein the compound is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and
 pharmaceutically acceptable salts thereof. 
 
     
     
       5. The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
       6. The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
       7. The compound of  claim 5 , further comprising a polyacetal scaffold that is conjugated to the compound at the hydroxyl group via a biodegradable bond wherein the resulting polyacetal-conjugated compound is useful for conjugating a protein based recognition-molecule (PBRM) that has a molecular weight of greater than 40 kDa. 
     
     
       8. The compound of  claim 7 , wherein the polyacetal scaffold comprises poly(1-hydroxymethylethylene hydroxymethyl-formal) (PHF) having a molecular weight ranging from 2 kDa to 40 kDa. 
     
     
       9. The compound of  claim 7  being 
       
         
           
           
               
               
           
         
         wherein 
         each occurrence of L P2  is independently a moiety containing a functional group that is yet to form a covalent bond with a functional group of the PBRM, and 
       
       
         
           
           
               
               
           
         
       
       between NH and L P2  denotes direct or indirect attachment of L P2  to NH;
 m is an integer from 1 to 300, 
 m 1  is an integer from 1 to 140, 
 m 2  is an integer from 1 to 40, 
 m 3  is an integer from 1 to 18, and 
 the sum of m, m 1 , m 2  and m 3  ranges from about 15 to about 300. 
 
     
     
       10. The compound of  claim 9 , wherein L P2  is selected from —SR p , —S—S-LG, maleimido, and halo, in which LG is a leaving group and R p  is H or a sulfur protecting group. 
     
     
       11. The compound of  claim 9 , wherein the PHF has a molecular weight ranging from 6 kDa to 20 kDa, m 2  is an integer from 2 to 20, m 3  is an integer from 1 to 9, and m 1  is an integer from 1 to 75, and the sum of m, m 1 , m 2 , and m 3  ranges from about 45 to about 150. 
     
     
       12. The compound of  claim 9 , wherein the PHF has a molecular weight ranging from 8 kDa to 15 kDa, m 2  is an integer from 2 to 15, m 3  is an integer from 1 to 7, and m 1  is an integer from 1 to 55, and the sum of m, m 1 , m 2 , and m 3  ranges from about 60 to about 110. 
     
     
       13. The compound of  claim 9 , further comprising a PBRM connected to the compound via L P2 . 
     
     
       14. A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       15. A pharmaceutical composition comprising a compound of  claim 5  and a pharmaceutically acceptable carrier. 
     
     
       16. A pharmaceutical composition comprising a compound of  claim 13  and a pharmaceutically acceptable carrier. 
     
     
       17. The compound of  claim 7 , wherein the PBRM has a molecular weight of greater than 80 kDa. 
     
     
       18. The compound of  claim 7 , wherein the PBRM is an antibody. 
     
     
       19. The compound of  claim 7 , wherein L P2  comprises a terminal group W P , in which each W P  independently is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         in which R 1K  is a leaving group, R 1A  is a sulfur protecting group, and ring A is cycloalkyl or heterocycloalkyl, and R 1J  is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety. 
       
     
     
       20. The compound of  claim 19 , wherein R 1A  is 
       
         
           
           
               
               
           
         
       
       in which r is 1 or 2 and each of R s1 , R s2 , and R s3  is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety.